RETRACTED ARTICLE: Metal free cross-dehydrogenative N-N coupling of primary amides with Lewis basic amines

Hydrazides, N-N containing structural motifs, are important due to their presence in a wide variety of biologically significant compounds. While the homo N-N coupling of two NH moieties to form the hydrazide N-N bond is well developed, the cross-dehydrogenative hetero N-N coupling remains very unevolved. Here we present an efficient intermolecular N-N cross-coupling of a series of primary benzamides with broad range of Lewis basic primary and secondary amines using PhI(OAc)2 as both a terminal oxidant and a cross-coupling mediator, without the need for metal catalysts, high temperatures, and inert atmospheres, and with substantial potential for use in the late-stage functionalization of drugs.

The manuscript titled "Transition Metal-Free Cross-Dehydrogenative Coupling of Primary Amides with Lewis Basic Primary and Secondary Amines for the Synthesis of Hydrazides: Application in Late-Stage Functionalization of Drugs" by S. Kathiravan, P. Dhillon, and I. A. Nicholls discusses a noteworthy method for the synthesis of hydrazides through N-N crosscoupling of benzamides and amines.The reaction utilizes PhI(OAc)2 both as an oxidant and a cross-coupling promoter.Despite the promising nature of the study and a thorough exploration of its scope, several areas require careful revision before publication in any scientific journal.1) Inaccuracies: Numerous inaccuracies exist within the manuscript: i) Several yields reported in tables differ from those in the Supplementary Information (e.g., 3l 85% vs. 98%; 5l 78% vs. 38%; 7j 35% vs. 32%).ii) Numerous compounds (at least 18) are named differently in the manuscript compared to the Supplementary Information, causing substantial reader confusion.iii) Two compounds, 7x and 7y, mentioned in the paper are not described in the Supplementary Information.iv) The names of compounds reported in the NMR spectra do not correspond to the names of the same compounds in the Supplementary Information (e.g., the NMR of compound 5k is labeled as 5j, the NMR of compound 5j is labeled as 5i, and the NMR of compound 5l is labeled as 5k, and so on).Furthermore, the 1H and 13C NMR spectra of compounds 3l and the 19F NMR spectra of N-(thiomorpholinyl)-3,5-bistrifluoromethylbenzamide are not included in the Supplementary Information.
2) Yield Assessment: The authors claim that the procedure is useful for pharmaceutical and drug synthesis.However, eight out of the twelve compounds in Scheme 5 were obtained with yields below 30% (four compounds with yields under 20%).This would be acceptable only if the nature and yield of obtained side products were reported to assess the mass balance.This same approach should be applied to species in Schemes 1-4 when yields are less than 50%.
3) Stoichiometry of Amines: The reported synthetic process consistently employs a stoichiometric excess of amines (amide:amine = 1:2).The question arises as to whether the reaction's efficiency is impacted when the correct stoichiometric ratio between the two reagents is used.This topic should be discussed to address this synthetic aspect.4) Reaction Mechanism: The proposed reaction mechanism is largely speculative and lacks support from experimental data.It would be beneficial to explore whether the presence of PhI and AcOH can be identified in the crude at the end of the reaction.This would lend more credibility to the proposed mechanism.5) Discussion Section: The section titled "Discussion" is more appropriately termed "Conclusion."This should be corrected to reflect the content accurately.6) -Minor Issues: i) When citing references, it would be more concise to report a range of references instead of listing all consecutive numbers.ii) The suggested mechanism must be labeled as "Scheme 6".
Overall, this manuscript shows potential but requires thorough revision to address to rectify the outlined issues.These improvements should be addressed, and the manuscript should then undergo reevaluation by referees before being considered for publication in a prestigious scientific journal such as Nature Communications.

Reviewer #2 (Remarks to the Author):
The present manuscript introduces the I(III)-mediated cross-coupling of amides with amines.While the concept is not new (as the authors rightly point out in refs 48-53, especially 53), the intermolecular dissymmetric cross-coupling has not been reported.The present paper introduces such a reaction.The authors provide a wide scope, with several amines and several amides.I feel however that the manuscript needs to be improved.The following items should be addressed or developed and/or clarified 1°) there are too many typos in the reaction descriptions.That is highly problematic for reproduction of the work.E. g. the footnotes of Schemes 2-4 still mention the use of 2, while the amines are renumbered in these schemes (4, 6 and 8 respectively).One supposes that it is also 2 equivalents of these amines, but who really knows?Meanwhile the general procedure in the SI reads "In an 10 mL screw cap reaction tube, benzamide (1 equiv.),PhI(OAc)2 (2 equiv.),K3PO4 (2 equiv.),1,2-dicloroethane (2 mL) was added under air to the reaction mixture and then allowed to warm to 80 °C for 18h(...)" When is the amine added?
2°) The scope should be commented more.Some of the results are odd.For instance, why do 7s and 7t behave so differently.Ditto for 7o and 7p.The authors skate over the differences too much in my opinion.To the best of my understanding, there are no real explanations as to where the rest of the SM go.It's ok maybe hen the yields are in the 80s, but less so when it is 15%ish.Do the authors evidence homocouplings?
3°) The mechanism suggested is very simplistic.Could the authors discuss why the amido/amino iodane reagent is formed preferentially relative to the other iodanes that could lead to the homocoupled products.Also is there an impact of steric bulk?And what happens in the absence of base.Does the AcOH released chew up some amine?It may be discussed in the references cited but I would like to see that discussed in the authors' system.After all, as they claim in the introduction, the previous report do not examine intermolecular hetero crosscoupling.So the literature should be also rediscussed through the authors' angle.

Reviewer #3 (Remarks to the Author):
Kathiravan and coworkers reported cross dehydrogenative N-N coupling of primary amides and Lewis basic primary and secondary amines with diacetoxyiodobenzene as the oxidant.However, the method is premature.The yields are generally low, which should be improved before publication.Actually, Patureau and coworkers disclosed a related cross dehydrogenative N-N coupling of methoxyamides with benzotriazoles as the oxidant (Org.Lett. 2021, 23, 10, 3902-3907).

Reviewer #1 (Remarks to the Author):
The manuscript titled "Transition Metal-Free Cross-Dehydrogenative Coupling of Primary Amides with Lewis Basic Primary and Secondary Amines for the Synthesis of Hydrazides: Application in Late-Stage Functionalization of Drugs" by S. Kathiravan, P. Dhillon, and I. A. Nicholls discusses a noteworthy method for the synthesis of hydrazides through N-N crosscoupling of benzamides and amines.The reaction utilizes PhI(OAc)2 both as an oxidant and a cross-coupling promoter.Despite the promising nature of the study and a thorough exploration of its scope, several areas require careful revision before publication in any scientific journal.1) Inaccuracies: Numerous inaccuracies exist within the manuscript: Answer: We have thoroughly revised the manuscript to ensure the accuracy and consistency of the content.
ii) Numerous compounds (at least 18) are named differently in the manuscript compared to the Supplementary Information, causing substantial reader confusion.Answer: The manuscript and associated Supplementary Information have been revised to address the issue of inconsistent naming for compounds.
iii) Two compounds, 7x and 7y, mentioned in the paper are not described in the Supplementary Information.Answer: These compounds are described in the Supplementary Information.
iv) The names of compounds reported in the NMR spectra do not correspond to the names of the same compounds in the Supplementary Information (e.g., the NMR of compound 5k is labeled as 5j, the NMR of compound 5j is labeled as 5i, and the NMR of compound 5l is labeled as 5k, and so on).Answer: The discrepancy in compound names between the NMR spectra and the Supplementary Information has been addressed.Furthermore, the 1H and 13C NMR spectra of compounds 3l and the 19F NMR spectra of N-(thiomorpholinyl)-3,5-bistrifluoromethylbenzamide are not included in the Supplementary Information.Answer: These spectra have been incorporated in the Supplementary Information.
2) Yield Assessment: The authors claim that the procedure is useful for pharmaceutical and drug synthesis.However, eight out of the twelve compounds in Scheme 5 were obtained with yields below 30% (four compounds with yields under 20%).This would be acceptable only if the nature and yield of obtained side products were reported to assess the mass balance.This same approach should be applied to species in Schemes 1-4 when yields are less than 50%.Answer: In response to the concerns raised about the yield assessment, we conducted a thorough reexamination of the reactions.After exploring various modifications, such as adjusting the stoichiometry of amines, reaction temperature, and solvent, we did not observe significant improvements in yield.Subsequently, a detailed analysis of Table 2 and 3 revealed that the incorporation of trifluoromethylated benzamides, particularly in Scheme 5, led to a substantial increase in yield, exceeding 50% in most of the cases.To address this, we have introduced these additional, new compounds into Schemes 4 and 5.This strategic use of 3,5-bis trifluoromethyl substituted benzamides consistently demonstrated higher reactivity, contributing to improved overall yields.We recognize the importance of transparency in reporting side products for mass balance assessment and have augmented the text to enhance the clarity of our findings, in particular in the case of the 4-methyl benzamides.
3) Stoichiometry of Amines: The reported synthetic process consistently employs a stoichiometric excess of amines (amide:amine = 1:2).The question arises as to whether the reaction's efficiency is impacted when the correct stoichiometric ratio between the two reagents is used.This topic should be discussed to address this synthetic aspect.Answer: Regarding the stoichiometry of amines, we conducted systematic screening experiments to assess the impact of varying the quantity of amines in the synthetic process.The control experiments, detailed in Table 1 entries 12-15, clearly demonstrated that an excess of the amine coupling partner is necessary to achieve an acceptable yield.We have now incorporated this critical information into the discussion, addressing the concern raised about the consistent use of a 1:2 ratio of amide to amine.Furthermore, leveraging the insights gained from these experiments, we have strategically adjusted the stoichiometry in cases where yields were initially below 50%.This iterative process has been instrumental in optimizing the reaction conditions and enhancing the overall efficiency of the synthetic procedure.The implications of this are discussed in relation to the proposed reaction mechanism.

S. No.
Amide: Amine stoichiometry Yield (%) 4) Reaction Mechanism: The proposed reaction mechanism is largely speculative and lacks support from experimental data.It would be beneficial to explore whether the presence of PhI and AcOH can be identified in the crude at the end of the reaction.This would lend more credibility to the proposed mechanism.
Answer: We conducted an analysis of the crude sample using LC-MS.Our findings revealed the presence of PhI and AcOH, providing experimental support for our proposed reaction pathway.Importantly, this observation aligns with previous reports (Ref. 85 & 95), further corroborating the credibility of the suggested mechanism.We have now included these findings in the manuscript.
5) Discussion Section: The section titled "Discussion" is more appropriately termed "Conclusion."This should be corrected to reflect the content accurately.
Answer: The section previously labeled "Discussion" has been appropriately revised to "Conclusion" to accurately reflect its content.
6) -Minor Issues: i) When citing references, it would be more concise to report a range of references instead of listing all consecutive numbers.Answer: We have addressed the suggestion to enhance citation conciseness by providing reference ranges instead of listing all consecutive numbers.
ii) The suggested mechanism must be labeled as "Scheme 6".Answer: The suggested mechanism has been appropriately relabeled as "Scheme 6." Overall, this manuscript shows potential but requires thorough revision to address to rectify the outlined issues.These improvements should be addressed, and the manuscript should then undergo reevaluation by referees before being considered for publication in a prestigious scientific journal such as Nature Communications.
We thank the reviewer for helpful comments.

Reviewer #2 (Remarks to the Author):
The present manuscript introduces the I(III)-mediated cross-coupling of amides with amines.While the concept is not new (as the authors rightly point out in refs 48-53, especially 53), the intermolecular dissymmetric cross-coupling has not been reported.The present paper introduces such a reaction.The authors provide a wide scope, with several amines and several amides.I feel however that the manuscript needs to be improved.The following items should be addressed or developed and/or clarified Answer: We appreciate the reviewer's acknowledgment of the novel contribution presented in the manuscript, specifically the introduction of intermolecular dissymmetric cross-coupling in I(III)-mediated cross-coupling of amides with amines.Recognizing the valuable feedback provided, we have taken steps to address and incorporate improvements for each of the points raised.
1°) there are too many typos in the reaction descriptions.That is highly problematic for reproduction of the work.Answer: The manuscript has been revised to remove typographical errors in the reaction descriptions.
E. g. the footnotes of Schemes 2-4 still mention the use of 2, while the amines are renumbered in these schemes (4, 6 and 8 respectively).One supposes that it is also 2 equivalents of these amines, but who really knows?Answer: The footnotes of Figures 2-4, which previously mentioned the use of 2 in relation to the amines that were renumbered (4, 6, and 8 respectively), have been updated for clarity.
Meanwhile the general procedure in the SI reads "In an 10 mL screw cap reaction tube, benzamide (1 equiv.),PhI(OAc)2 (2 equiv.),K3PO4 (2 equiv.),1,2-dicloroethane (2 mL) was added under air to the reaction mixture and then allowed to warm to 80 °C for 18h(...)" When is the amine added?Answer: We have addressed this issue and provided the necessary clarification.The amended procedure now clearly specifies when the amine is added to the reaction mixture.(SI page No. 9) 2°) The scope should be commented more.Some of the results are odd.For instance, why do 7s and 7t behave so differently.Answer: We have incorporated a more detailed discussion to provide additional insights and explanations for these observations.Additional reactions, e.g.3,5-bistrifluoromethyl derivatives, have been performed providing further basis for this discussion.(Page 5) Ditto for 7o and 7p.
Answer: Similar to the case of 7s and 7t, we have now provided a more detailed discussion regarding the observed differences in behavior between 7o and 7p.(Page 5).
The authors skate over the differences too much in my opinion.
Answer: We agree that the differences were not sufficiently addressed, and we have taken steps to rectify this by providing a more detailed discussion.
To the best of my understanding, there are no real explanations as to where the rest of the SM go.It's ok maybe then the yields are in the 80s, but less so when it is 15%ish.
Answer: Upon further consideration, we agree with the reviewer that clearer explanations regarding the fate of the remaining starting materials is necessary, especially when yields are lower, around 15%.In response to this concern, we have explicitly noted instances where unreacted starting materials were observed in cases where the reaction yield is less than 70%.

Do the authors evidence homocouplings?
Answer: The inquiry about evidence of homocouplings has been considered.Under the optimized reaction conditions, no evidence of homo-coupled products was observed.However, it is worth noting that a trace quantity was detected in the crude LC-MS when the reaction was conducted solely with benzamide, without the amine.(Page No. 7).
3°) The mechanism suggested is very simplistic.Could the authors discuss why the amido/amino iodane reagent is formed preferentially relative to the other iodanes that could lead to the homocoupled products.
Answer: The reviewer rightly pointed out the simplicity of the suggested mechanism, specifically questioning why the amido/amino iodane reagent is formed preferentially over other iodanes that could lead to homocoupled products.Also is there an impact of steric bulk?Answer: The potential impact of steric bulk has been considered.When utilizing bulky amine derivatives, we observed a direct influence on both yield and reactivity.This suggests that steric considerations play a role in the reaction outcomes.This is now better described in the text.(Page No. 5).
And what happens in the absence of base.
Answer: The impact of the absence of a base was explored, revealing a significant reduction in yield.Specifically, in Table 1, entry -10, we observed a substantial loss in yield when the reaction was conducted in the absence of a base.This observation underscores the importance of the base in the reaction and its role in achieving satisfactory yields.We have now better highlighted this in the text.(Page No. 3) Does the AcOH released chew up some amine?It may be discussed in the references cited but I would like to see that discussed in the authors' system.Answer: The interaction of released AcOH with amine has been addressed by LC-MS studies of the crude reaction mixture, where the presence of AcOH was identified.This is expected to protonate the amine, and is concluded to be the basis for the need of a 1:2 amide-amine stoichiometry.These studies and the consequences for the reaction mixture have now been presented in the text.(Page No. 7) After all, as they claim in the introduction, the previous report do not examine intermolecular hetero crosscoupling.So the literature should be also rediscussed through the authors' angle.
Answer: We have re-angled our literature discussion as suggested by highlighting the importance of hetero cross-coupling early in the literature background presentation.
Reviewer #3 (Remarks to the Author): Kathiravan and coworkers reported cross dehydrogenative N-N coupling of primary amides and Lewis basic primary and secondary amines with diacetoxyiodobenzene as the oxidant.However, the method is premature.Answer: We believe these revisions contribute to a more comprehensive understanding of our work.
The yields are generally low, which should be improved before publication.
Answer: Acknowledging the concern about generally low yields, we have taken significant steps to address this issue.By strategically changing the substituent on benzamide, specifically using 3,5-bistrifluoromethyl benzamide (1r) in cases where lower yields were observed with 4-methyl benzamide, we have achieved a substantial improvement in reactivity.The reoptimized conditions have resulted in product yields exceeding 50% in almost all studied reactions.This observation underscores the substituent-dependent reactivity of the reaction.